Biology subjects

Danger, R.

Publications and source records attributed to Danger, R..

5 recordsLinked to original sources

bioRxiv2026

Molecular and spatial profiling identifies immune endotypes for the stratification of OA patients

Osteoarthritis (OA) is a prevalent and heterogeneous joint disease in which synovial inflammation drives structural progression and pain. Despite the recognized heterogeneity of OA, the cellular and molecular organization of synovial tissue remains poorly characterized and defining distinct histological and immune endotypes could guide precision medicine and therapeutic targeting. We show that histologically defined synovial pathotypes are conserved across independent cohorts and correspond to distinct molecular immune endotypes. Integration of bulk and spatial transcriptomics with proteomics revealed niche-specific gene and protein signatures, reflecting the anatomical and functional diversity of OA synovium. The lympho-myeloid pathotype was characterized by mature ectopic lymphoid structures containing CD21+CD23+ follicular dendritic cells, spatially organized T and B cell zones, and clonally expanded T and B cells with shared immune cell receptor motifs, consistent with local adaptive immune activity correlating with radiological joint damage. These findings highlight how immune organization and cellular composition shape OA pathogenesis and provide a framework for endotype-guided stratification and therapeutic targeting.

immunology↗

bioRxiv2024

Transcriptomic, clonal, and functional analyses reveal Liver tissue-imprinted immuno-profile of circulating autoreactive CD4 T cells in autoimmune liver diseases

Autoimmune liver diseases (AILD) are immune-mediated disorders in which CD4 T cells play a central role. However, the link between circulating self-antigen-specific CD4 T cells and the targeted tissue has not been extensively studied in AILD. We hypothesized that circulating autoreactive CD4 T cells were clonally and functionally related to dominant intra-hepatic pathogenic CD4 T cell clones. Single cell transcriptomic analysis of circulating self-antigen-specific CD4 T cells revealed a specific B-helper and immuno-exhausted transcriptional profile, which was conserved for different autoantigens, but distinct from several other types of foreign antigen specificities. In the blood, the dominant hepatic CD4 T cell clones had a similar transcriptomic signature and were enriched in the PD-1+ TIGIT+ HLA-DR+ CD4 T cell subset. In a mouse model, antigen-specific CD4 T cells acquired the immuno-exhausted transcriptional profile when they accumulated in the liver after local antigen reactivity. Locally, immune checkpoint molecules controlled the response of antigen-specific CD4 T cells responsible for liver damage. Our study reveals the origin and biology of liver-derived autoreactive CD4 T cells in the blood of AILD patients that are imprinted by the liver environment, and suggest a dysregulation of the immune checkpoint molecules pathways. Our study enables tracking and isolating circulating autoreactive CD4 T cells for future diagnostic and therapeutic purposes.

immunology↗

bioRxiv2023

A gene-expression module in circulating immune cells is associated with cell migration during immune diseases.

Circulating immune cells are critical mediators of inflammation upon recruitment to tissues, yet how their gene expression state influences this recruitment is not well understood. Here, we report longitudinal single-cell transcriptome profiling of peripheral blood mononuclear cells in patients undergoing kidney transplantation rejection. We identify a novel gene expression module, termed ALARM (early activation transcription factor module), associated with transcriptional regulation, homing, and immune activation across multiple immune cell types. Circulating cells expressing this module are significantly reduced in patients experiencing graft rejection, a finding confirmed in a pig model of acute kidney transplantation rejection. Correspondingly, module expression is markedly increased in kidney grafts undergoing rejection, indicating preferential recruitment of ALARM-expressing cells to the inflamed tissue. Within this module, we identify the receptor CXCR4 and its ligand CXCL12, expressed in the graft, as a likely mechanism for recruitment. In vitro transwell assays combined with scRNA-seq reveal that this CXCR4-CXCL12 interaction is critical for T cell migration and upregulation of CD69, an early activation marker, and is accompanied by a metabolic switch towards glycolysis. Further exploration of publicly available transcriptomic data demonstrates that this module is generally expressed in healthy individuals and is strongly associated with responses to infection, including SARS-CoV-2 infection. This finding is further supported by experiments in a pneumonia mouse model, which confirm the recruitment of CXCR4-expressing T cells during lung infection. Moreover, we find that module expression is predictive of immune-mediated diseases. In summary, we have identified a key gene expression module in circulating immune cells that orchestrates their preferential recruitment to inflamed tissues, metabolic reprogramming, promoting tissue residency and effector functions. These insights advance our understanding of immune cell recruitment and activation mechanisms in transplant rejection and infectious diseases, with potential implications for therapeutic interventions.

immunology↗

bioRxiv2022

Preclinical model for the study of immune responses specific for a hepatic self-antigen

The liver displays a strong capacity to induce tolerance toward hepatic antigens. However, hepatic tolerance can be overcome with the development of local autoimmune diseases such as autoimmune hepatitis (AIH). This chronic inflammatory disorder leads to a progressive destruction of liver parenchyma if non-treated. Although the CD4+ T cell response seems a key player of this immune disorder, the dynamics and biology of emerging liver antigen-specific CD4+ T cells are poorly described. Here, we developed a new murine model which mimics hepatic autoreactivity allowing the study and monitoring of antigen-specific CD4+ T cells from their emergence to local immune response. We show that the induction of the expression of an antigen in the liver in non-inflammatory condition leads to antigen tolerance. In inflammatory condition, using viral vector transduction, we observe the development of a complete adaptive immune response concomitant with the antigen expression in the liver. The presence of antigen-specific CD4+ T cells in the liver is associated to transient hepatic damages. Interestingly, the neo-antigen expression by hepatocytes after peripheral immunisation induces the recruitment of antigen-specific CD4+ T cells and hepatic damages. These data demonstrate that the recruitment of antigen-specific CD4+ T cells in the liver is conditioned by an immune coordination between surface antigen expression by hepatocytes and peripheral immune response and mimics the first step of a local autoreactive process. In the long-term, we observe that the hepatic environment has the capacity to control the local, but not the systemic, antigen-specific CD4+ T cells. Additional immune events might be involved in the long-term chronic immune reactivity in the liver, following the first steps described in this study. Key pointsO_LIAntigen expression in the liver in non-inflammatory condition leads to antigen tolerance C_LIO_LIAntigen expression in the liver in immunization condition (concomitant or pre-existing) is sufficient to induce liver recruitment of antigen-specific CD4+ T cells and hepatic damages C_LIO_LIThis model mimics the first step of an autoreactive process against a liver antigen C_LIO_LIIn the long-term, the hepatic environment induces a local tolerance toward the antigen expression and the clearance of liver-infiltrating, but not peripheral, antigen-specific CD4+ T cells C_LIO_LIThis new murine model can be of interest for the analysis of the immunomodulatory pathways implicated in liver tolerization of autoreactive CD4+ T cells and identification of potential extrinsic factors implicated in an acute-to-chronic transition as observed during autoimmune hepatitis C_LI

immunology↗

bioRxiv2020

FaDA: A Shiny web application to accelerate common lab data analyses

BackgroundWeb-based data analysis and visualization tools are mostly designed for specific purposes, such as data from whole transcriptome RNA sequencing or single-cell RNA sequencing. However, limited efforts have been made to develop tools designed for data of common laboratory data for non-computational scientists. The importance of such web-based tool is stressed by the current increased samples capacity of conventional laboratory tools such as quantitative PCR, flow cytometry or ELISA. ResultsWe provide a web-based application FaDA, developed with the R Shiny package providing users to perform statistical group comparisons, including parametric and non-parametric tests, with multiple testing corrections suitable for most of the standard wet-lab analyses. FaDA provides data visualization such as heatmap, principal component analysis (PCA) and receiver operating curve (ROC). Calculations are performed through the R language. ConclusionsFaDA application provides a free and intuitive interface allowing biologists without bioinformatic skills to easily and quickly perform common lab data analyses. The application is freely accessible at https://shiny-bird.univ-nantes.fr/app/Fada AbbreviationsAUC: Area Under the Curve; FaDA: Fast Data Analysis; GEO: Gene Expression Omnibus; ELISA: enzyme-linked immunosorbent assay; PCA: Principal Component Analysis; qPCR: quantitative PCR; ROC: Receiver Operating Curve.

bioinformatics↗